http://www.ncbi.nlm.nih.

gov/pmc/articles/PMC3577063/
Prog Retin Eye Res. Author manuscript; available in PMC 2014 Mar 1.
Published in final edited form as:
Prog Retin Eye Res. 2013 Mar; 33: 6784.
Published online 2012 Nov 29. doi: 10.1016/j.preteyeres.2012.11.001
PMCID: PMC3577063
NIHMSID: NIHMS423344

Amblyopia and Binocular Vision

Eileen E. Birch1,2
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Abstract
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1. Introduction
1.1 Amblyopia

Amblyopia is diminished vision that results from inadequate visual experience during the
first years of life. Typically, amblyopia is clinically defined as reduced visual acuity
accompanied by one or more known amblyogenic factors, such as strabismus, anisometropia,
high refractive error, and cataract. Amblyogenic factors interfere with normal development of
the visual pathways during a critical period of maturation. The result is structural and
functional impairment of the visual cortex, and impaired form vision.
Although amblyopia can be bilateral, it most commonly affects one eye of children with
strabismus, anisometropia, or both. The prevalence of strabismus, anisometropia, and
amblyopia has been reported in a number of recent population-based studies of preschool
children and school children in the United States, the United Kingdom, Netherlands,
Sweden, and Australia (Table 1).

Table 1
Prevalence of strabismus, anisometropia, and amblyopia in recent (20012012) populationbased studies of children.
Overall, results of the studies are consistent, with a mean prevalence of 2.8% for strabismus,
3.5% for anisometropia, and 2.4% for amblyopia. With 625 million children under the age of
5 years worldwide, more than 15 million may have amblyopia, and more than half of them
will not be identified before they reach school age. (Wu and Hunter, 2006) Many affected
children will suffer irreversible vision loss that could have been prevented. The consequences
of not identifying and treating strabismus and amblyopia early include permanent visual
impairment, adverse effects on school performance, poor fine motor skills, social
interactions, and self-image.(Choong et al., 2004; Chua and Mitchell, 2004; Horwood et al.,
2005; OConnor et al., 2010b; OConnor et al., 2009; Packwood et al., 1999; Rahi et al.,
2006; Webber et al., 2008a, b) Importantly, permanent monocular visual impairment due to
amblyopia is a risk factor for total blindness if the better eye is injured or if the fellow eye is
affected by disease later in life.(Harrad and Williams, 2003)
The predominant theory is that amblyopia results when there is a mismatch between the
images to each eye; one eye is favored while the information from the other eye is
suppressed.(Harrad et al., 1996) Because amblyopia typically affects visual acuity in one eye,
amblyopia is often considered to be a monoculardisease. Thus, the mainstay of treatment for
amblyopia has been patching of the normal fellow eye to improve the monocular function of
the amblyopic eye. However, there are significant shortcomings to this approach to
understanding and treating amblyopia. Our research studies on amblyopia have revealed that
binocular dysfunction plays an important role in amblyopia and has laid the groundwork for
a new approach for the development of more effective treatment.
1.2 Clinical Profile of Amblyopia

Two large studies have defined the clinical profile of amblyopic children.(Birch and Holmes,
2010; Pediatric Eye Disease Investigator Group, 2002a) Both studies included children with
strabismic, anisometropic, or combined-mechanism amblyopia referred by multiple
community- and university-based pediatric ophthalmologists. In the Pediatric Eye Disease
Investigator Group (PEDIG) study, we assessed the clinical characteristics of 409 children

age 36.9 years with moderate amblyopia who were enrolled in a multicenter randomized
study of amblyopia treatment.(Pediatric Eye Disease Investigator Group, 2002a) Strabismus
or anisometropia each accounted for about 40% of amblyopia, with just over 20% of
amblyopia in children with both strabismus and anisometropia (Figure 1). Overall, mean
refractive error in the amblyopic eye was +4.52 D and in the fellow eye was +2.83D, but
fellow eye refractive error was higher in the strabismic children (+3.54 D) and lower in the
anisometropic children (+1.95 D).

Figure 1
In the<3-year-old cohort,(Birch and Holmes, 2010) 82% of amblyopia was associated with
strabismus, 5% with anisometropia, and 13% with combined mechanisms. This finding is
strikingly different from the PEDIG 3- to 6-year-old cohort,(Pediatric ...
In a second study, we examined the clinical profile of 250 amblyopic children less than 3
years old in the Dallas area (Birch and Holmes, 2010); 82% of amblyopia was associated
with strabismus, 5% with anisometropia, and 13% with both (Figure 1), a strikingly different
distribution of amblyogenic factors compared with the older cohort. Mean refractive error in
the amblyopic eye was +2.63 D, substantially lower than in the older cohort. Fellow eye
refractive error averaged +2.60 D, similar to the overall mean for the older cohort and, as
with the older cohort, fellow eye refractive error was higher in the strabismic children (+2.59
D) and lower in the anisometropic children (+0.94D). Our studies, along with two additional
studies from the UK (Shaw et al., 1988; Woodruff et al., 1994b), suggest that the factors
responsible for amblyopia vary with age (Figure 2). Strabismus is the overwhelmingly the
factor most associated with amblyopia during the first year. Anisometropia, either alone or in
combination with strabismus, becomes equally prominent as a cause of amblyopia by the
third year and, by the fifth year, is the causative factor in nearly two-thirds of amblyopic
children.

Figure 2
Strabismic amblyopia was diagnosed much more commonly than anisometropic or
combined-mechanism amblyopia in children<3 years of age.(Birch and Holmes, 2010) This
finding is in sharp contrast to the PEDIG report of approximately equal proportionsof ...

The low percentage of amblyopia attributable to anisometropia in the<3 year cohort is

unlikely to be the result of marked under-referral of anisometropia in this age range. Overall,
in the parent study from which the amblyopic children <3 years old were drawn, only 18% of
the 67 of anisometropic children were diagnosed with amblyopia.(Birch and Holmes, 2010)
In contrast, almost 50% of the 396 children with strabismus or strabismus with
anisometropia were diagnosed with amblyopia. This suggests that anisometropia may
develop later, and become an etiologic factor for amblyopia primarily after 3 years of age.
Another alternative is that anisometropia may be present early but requires a longer duration
than strabismus to cause amblyopia.
1.3 Amblyopia Treatment

Current treatments for amblyopia rely on depriving the healthy, fellow eye of vision to force
use of the amblyopic eye. The assumption is that the primary deficit in amblyopia is a
monocular visual acuity deficit caused by preference for fixation by the fellow eye. By
depriving the fellow eye of vision, suppression of the amblyopic eye is eliminated and visual
experience will promote development or recovery of visual acuity. Patching, atropine, and
filters that penalize the fellow eye have been used to treat amblyopia for hundreds of years.
(Loudon and Simonsz, 2005) Only in the last 15 years have randomized clinical trials been
conducted to evaluate the effectiveness of amblyopia treatment and to begin to define
optimal treatment protocols. The Pediatric Eye Disease Investigator Group (PEDIG) has
conducted a series of randomized clinical trials of amblyopic treatment for children ages 3
17 years old. To date, our major results are:
A period of 1622 weeks of treatment with optical correction alone leads to an
improvement of 0.2 logMAR (2 lines) in both children with anisometropic
amblyopia (Cotter et al., 2006) and children strabismic or combined mechanism
amblyopia. (Cotter et al., 2012) In nearly one-third of amblyopic children treated with
optical correction, amblyopia completed resolved. Similar results have been reported
by the Monitored Occlusion Treatment of Amblyopia Study (MOTAS) Cooperative
Group, and the Randomized Occlusion Treatment of Amblyopia (ROTAS)
Cooperative Group studies. (Stewart et al., 2011) Thus, refractive correction as the
sole initial treatment for amblyopia is a viable option.
Patching is an effective treatment for amblyopia. After stable visual acuity was
achieved with spectacle wear, 3- to 7-year-old amblyopic children who were
randomized to patching treatment had further visual acuity improvement of 0.22
logMAR (2.2 lines).(Wallace et al., 2006)

 For moderate amblyopia, a prescribed patching dose of 2 hr/day results in the same
visual acuity outcome as a prescribed patching dose of 6 hr/day(Repka et al., 2003)
and, for severe amblyopia, 6 hr/day yields similar results to 12 hr/day.(Holmes et al.,
2003) Objective monitoring of compliance with prescribed patching in a similar UK
study suggests that the similar visual acuity outcomes may have been due to lack of
compliance with the higher prescribed doses; i.e., the two treatment groups may have
actually received similar doses despite assignment to different doses.(Stewart et al.,
2007b)
Atropine and patching result in similar improvements in visual acuity when used as
the initial treatment of moderate amblyopia in children aged 3 - 6 years. (Pediatric
Eye Disease Investigator Group, 2002b) Most children had 0.3 logMAR (3 lines)
improvement in visual acuity and about 75% achieved 20/30 or better visual acuity
within 6 months. (Pediatric Eye Disease Investigator Group, 2002b)
Among children with severe amblyopia (>0.7 logMAR), treatment on weekends with
atropine led to an average improvement of 0.45 logMAR (4.5 lines). (Repka et al.,
2009)
Treatment of amblyopia can be effective beyond 7 years of age, although the rate of
response to treatment may be slower, may require a higher dose of patching, and the
extent of recovery may be less complete.(Holmes et al., 2011; Pediatric Eye Disease
Investigator Group, 2003, 2004)
The PEDIG results, along with results from MOTAS and ROTAS are summarized in Figure
3.

Figure 3
Summary of results from recent randomized clinical trials for the treatment of amblyopia
conducted by the Pediatric Eye Disease Investigator Group (PEDIG) (Holmes et al.,
2006; Quinn et al., 2004;Repka and Holmes, 2012), the Monitored Occlusion Treatment ...
1.4 Failures of Amblyopia Treatment

Not all amblyopic children achieve normal visual acuity despite treatment. Although 7390%
have improvements in visual acuity with various treatment modalities alone or in
combination,(Repka et al., 2003;Repka et al., 2004; Repka et al., 2005; Rutstein et al.,

2010; Stewart et al., 2004b; Wallace et al., 2006) 1550% fail to achieve normal visual
acuity even after extended periods of treatment. (Birch and Stager, 2006;Birch et al.,
2004; Repka et al., 2003; Repka et al., 2004; Repka et al., 2005; Rutstein et al.,
2010; Stewart et al., 2004b; Wallace et al., 2006; Woodruff et al., 1994a) One possible
explanation for the failure to achieve normal visual acuity is that the treatment was started
too late.
Both experimental and clinical data support the hypothesis that there is an early sensitive
period during which strabismus and anisometropia can lead to abnormal visual development,
conventionally considered to be the first 7 years of life. As a consequence, there is also a
widely held assumption that treatment during this early period is critical for obtaining
optimal visual acuity outcome. A recent meta-analysis of 4 multi-center amblyopia treatment
studies (Holmes et al., 2011) reported that 7- to 13-year-old children were significantly less
responsive to amblyopia treatment than children less than 7 years old. However, the metaanalysis failed to find a significant difference in treatment response between the 3- and 4year olds and the 5- and 6-years olds. On the one hand, these results appear to support the
concept of a critical period for treatment that coincides with the critical period for visual
development. On the other hand, poor response to treatment among older children could
simply reflect poor compliance with treatment; none of these treatment studies included an
objective measure of compliance with patching and glasses. In fact, we have observed
approximately the same prevalence of unresolved amblyopia in children whose amblyopia
treatment was initiated during the first year of life (Birch and Stager, 2006; Birch et al.,
1990; Birch et al., 2004) as we and others have observed when treatment is not initiated until
36 years of age. (Birch and Stager, 2006; Birch et al., 2004; Repka et al., 2003; Repka et al.,
2004; Repka et al., 2005; Rutstein et al., 2010; Stewart et al., 2004b; Wallace et al.,
2006; Woodruff et al., 1994a) This suggests that delay in treatment is not the sole reason for
failure to recover normal visual acuity.
An alternative explanation for failure to achieve normal visual acuity is lack of compliance
with treatment. Using objective occlusion dose monitoring devices, it has been demonstrated
that compliance varies widely among children treated for amblyopia and that visual acuity
outcome is related to compliance. (Loudon et al., 2002, 2003; Stewart et al., 2004b; Stewart
et al., 2007a, b) Randomized clinical trials have supported the use of educational and
motivational material for the children and the parents to improve compliance.(Loudon et al.,
2006; Tjiam et al., 2012) However, none of these studies has yet demonstrated that improved
compliance reduces the proportion of children who fail to achieve normal visual acuity with
amblyopia treatment.

A third possible reason for failure to achieve normal visual acuity with standard treatments
for amblyopia is that current treatments are inadequate. In other words, perhaps more
intensive treatment is needed as a final push to overcome residual amblyopia. Recently, the
Pediatric Eye Disease Investigator Group conducted a multi-center randomized clinical trial
for children with residual amblyopia do 0.20.5 logMAR who had stopped improving with 6
hours of prescribed daily patching or daily atropine.(Wallace et al., 2011a) We found that an
intensive combined treatment of patching and atropine did not result in better visual acuity
outcomes after 10 weeks compared with a control group in which treatment was gradually
discontinued.
Finally, it has been suggested that children who fail to recover normal visual acuity with
standard amblyopia treatments may have subtle retinal, optic nerve, or gaze control
abnormalities that limit their potential for visual acuity recovery. (Giaschi et al.,
1992; Lempert, 2000, 2003, 2004, 2008a, b) Abnormal macular thickness (Al-Haddad et al.,
2011; Altintas et al., 2005; Dickmann et al., 2009; Huynh et al., 2009; Walker et al., 2011),
optic disc dysversion (Lempert and Porter, 1998), optic nerve hypoplasia (Lempert, 2000),
and gaze instability (Regan et al., 1992) have all been described in subsets of patients with
amblyopia. To evaluate whether changes in the retina, optic nerve, or gaze control may limit
some childrens response to amblyopia treatment, we evaluated each of these aspects of the
visual system in 26 children with persistent residual strabismic, anisometropic, or combined
mechanism amblyopia. We compared the retina, optic nerve, and gaze control characteristics
of their amblyopic eyes with those of the fellow eyes, with age-matched nonamblyopic
children who had strabismus or anisometropia (n-12), and with age-matched normal controls
(n=48). (Subramanian et al., in press) All amblyopic children had been treated with glasses,
patching, and/or atropine for 0.85 years, had a residual visual acuity deficit, and no
improvement in visual acuity despite treatment and excellent compliance for at least 6
months prior to enrollment.
Images of the macula were obtained with the Spectralis (Heidelberg Engineering) spectral
domain OCT (SD-OCT) using the eye-tracking feature (ART). Each child had one to three
line scans centered on the optic disc to measure horizontal and vertical disc diameter, and
one to three 3mm high-resolution peripapillary RNFL circular scans, and one to three highresolution macular volume scans. Optic disc dysversion (tilt) was quantified by calculating
the ratio of vertical to horizontal disc diameters. Optic nerve hypoplasia was quantified by
calculating the area of the ellipse specified by the vertical and horizontal diameters. In order
to assess possible sectoral hypoplasia,(Lee and Kee, 2009) RNFL thickness was
automatically segmented using the Spectralis software that provided average thickness
measurements for each of 6 RNFL sectors centered on the optic disc [temporal superior (TS),
temporal (T), temporal inferior (TI), nasal inferior (NI), nasal (N), nasal superior (NS)]

together with a global average (G). Total macular thickness and sectional volumes were
automatically determined by software provided by Heidelberg Engineering for the Spectralis
SD-OCT, using a modified ETDRS circle grid (center, middle and outer rings: 1, 2, and 3
mm). To assess gaze control, eye movements during attempted steady fixation in primary
gaze (binocular and monocular) were recorded using an infrared eye tracker.
As shown in Figure 4, no abnormalities were apparent in macular structure, and there were
no significant differences in macular thickness between the amblyopic and fellow eyes,
nonamblyopic eyes, or normal control eyes. Nor were there significant differences among
these groups in optic disc diameter or shape (dysversion), or in peripapillary RNFL thickness
(Figure 4). Children with persistent amblyopia had eye movement abnormalities in both
amblyopic and fellow eyes, including infantile nystagmus (13%), fusion maldevelopment
nystagmus (47.8%), and saccadic oscillations (39.1%). Some non-amblyopic eyes of children
with strabismus or anisometropia also had saccadic oscillations (44.4%) or fusion
maldevelopment nystagmus (11.1%). Normal controls showed no gaze abnormalities. Thus,
retinal and optic nerve abnormalities cannot explain persistent amblyopia. Gaze instabilities
are typically bilateral, but may be a plausible explanation of persistent amblyopia in a subset
of children who have asymmetric gaze instability (more instability in the amblyopic eye).

Figure 4
Spectral domain optical coherence tomography (SD-OCT) scans of the amblyopic (top left)
and non-amblyopic (top right) eyes of a child with persistent amblyopia.(Subramanian et al.,
in press) Overall (n=26), there were no significant differences in total ...
Even among the 5085% of children who do achieve normal visual acuity with amblyopia
treatment, the risk for recurrence of amblyopia is high. In a series of prospective,
longitudinal studies of infantile and accommodative esotropia conducted in our laboratory
over the past 22 years,(Birch, 2003; Birch et al., 2005;Birch and Stager, 2006; Birch et al.,
1990; Birch et al., 2004; Birch et al., 2010) 80% of esotropic children were treated for
amblyopia at least once during the first 5 years of life; 60% had recurrent amblyopia that
required retreatment during the 5-year follow-up. PEDIG reported that 25% of successfully

treated amblyopic children experience a recurrence within the first year off treatment.
(Holmes et al., 2004)
1.5 Insights from Treatment Failures

Residual and recurrent amblyopia remain unexplained. The studies reviewed in Sections 1.3
and 1.4 all have one important feature in common; amblyopia treatment was monocular. Yet
the predominant theory is that amblyopia arises when there is a mismatch between the
images to each eye. In other words, abnormal binocular experience is the primary cause. This
prompted us to investigate the link between amblyopia and binocular function from a number
of different approaches. Our investigations have evaluated the role of binocular dysfunction
in the disproportionate loss of optotype visual acuity in strabismic amblyopia (Section 2.1),
in the risk for persistent, residual amblyopia (Section 2.2), in asymmetric fusional
suppression (Section 2.3), in the gaze instabilities associated with amblyopia (Section 2.4,
and in the fine motor skill deficits that are present in amblyopic children and adults (Section
2.5). As evidence about the primary role of binocular dysfunction in amblyopia has
accumulated, we have worked to develop approaches to amblyopia treatment (Section 3).
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2. Amblyopia and Binocular Vision
2.1 Stereoacuity and Amblyopia

Strabismic and anisometropic amblyopia differ in the spectrum of associated visual deficits
despite their common effect on visual acuity. Strabismic amblyopia is associated with
disproportionately greater deficits in optotype visual acuity and vernier acuity compared with
grating acuity, but anisometropic amblyopia is associated with proportional deficits in
optotype, vernier, and grating acuity. (Levi and Klein, 1982; Levi and Klein, 1985) There are
two hypotheses regarding the source of differences in the pattern of visual deficits between
anisometropic and strabismic amblyopia. First, the differences may reflect fundamentally
different pathophysiological processes (etiology hypothesis).(Levi, 1990; Levi and Carkeet,
1993) For example, sparse/irregular sampling may be associated with binocular competition
between two discordant images in strabismus but not between the sharp versus defocused
images in anisometropia. The second hypothesis is that the different constellations of spatial
deficits in anisometropic and strabismic amblyopia reflect the degree of visual maturation
present at the onset of amblyopia (effective age hypothesis);(Levi, 1990; Levi and Carkeet,
1993) that is, anisometropic amblyopia may arise at an age where visual maturation is more
complete. The low prevalence of anisometropic amblyopic in children <3 years old (Section
1.2) is consistent with the effective age hypothesis. The effective age hypothesis predicts that

visual functions that mature earliest will be less susceptible to disruption by abnormal visual
experience. Much of the data from adult with amblyopia is consistent with both of these
ideas but direct tests of the alternative hypotheses were not possible in adults because
complete clinical histories are rarely available to precisely document etiology and the time
course over which amblyopia developed.
We designed a study to overcome this limitation by evaluating vernier, resolution and
recognition acuities of amblyopic children who were enrolled in a prospective study of visual
maturation during infancy and early childhood, i.e. amblyopic children with known age of
onset and etiology. (Birch and Swanson, 2000) We found that strabismic amblyopia, whether
it had infantile onset or preschool age onset, was associated with disproportionately larger
optotype and vernier acuity deficits compared to grating acuity deficits (Figure 5). Moreover,
looking only at the subgroup of amblyopic children with infantile onset (Figure 5), we
observed differences in the pattern of visual deficits. Children with infantile strabismic
amblyopia had disproportionately larger optotype and vernier acuity deficits compared to
grating acuity deficits but children with infantile anisometropic amblyopia had proportional
deficits in optotype, vernier, and grating acuity. These data support the etiology hypothesis.
Infantile anisometropic amblyopia results from blurred vision in one eye during the first
years of life; in infant monkeys, experimentally induced blur leads to a selective loss of
neurons tuned to high spatial frequencies. (Kiorpes et al., 1998; Kiorpes and McKee, 1999)
On the other hand, infantile strabismus disrupts the binocular connections of cortical neurons
and can lead to the development of a fixation preference for one eye and a constellation of
monocular visual deficits in the non-preferred eye in which optotype and vernier acuity are
especially compromised. (Kiorpes et al., 1998;Kiorpes and McKee, 1999) However, it is
important to note that anisometropic amblyopia, whose eyes are aligned but who lack central
binocular function, resemble those with strabismic amblyopia in their pattern of visual
deficits. (Levi et al., 2011) Thus, it appears that the presence or absence of binocular function
drives the pattern of visual deficits, not the presence or absence of strabismus.

Figure 5
Grating acuity and vernier acuity at 69 years of age for 20 amblyopic children enrolled in a
prospective study at the time of diagnosis during infancy.(Birch and Swanson, 2000) The
solid line shows the predicted relationship if comparable deficits ...

We tested the hypothesis that regardless of the etiology of amblyopia, those who have nil
stereoacuity experience a disproportionate loss in optotype acuity, and this loss exceeds what
is seen in amblyopia with preserved stereopsis.(Bosworth and Birch, 2003) Optotype acuity,
Teller grating acuity, and stereoacuity were evaluated in 106 children with moderate
amblyopia (0.3 0.7 logMAR) due to anisometropia, strabismus, or both. Overall,
amblyopic children had 2 times worse optotype acuity than grating acuity. Regardless of age
at onset or etiology, amblyopic children with nil stereoacuity had large optotype-grating
acuity discrepancies (Figure 6), Our data suggest that the residual monocular sampling
mosaic provides adequate information for grating detection but is inadequate to represent the
local spatial relationships needed for optotypes. These data support the hypothesized link
between impaired binocular function and the neural undersampling/disarray associated with
amblyopia.

Figure 6
Grating and optotype acuities for 106 children with mild-to-moderate amblyopia.(Bosworth
and Birch, 2003) Amblyopic children with preserved stereopsis (grey symbols) fall near the
1:1 line (gray line), consistent with similar loss of grating acuity and ...
2.2 Risk Factors for Persistent Amblyopia

Independent support for a strong link between binocular dysfunction and amblyopia has
come from our studies of persistent residual amblyopia. To evaluate potential risk factors for
persistent amblyopia,(Birch et al., 2007) we enrolled 130 consecutive children with infantile
esotropia or accommodative esotropia in a prospective, longitudinal study at the time of their
initial diagnosis, and conducted regular follow-up visits to assess visual acuity and
stereoacuity through visual maturity (mean age = 9.5 years). On the basis of the longitudinal
data set, the children were classified as: never amblyopic, recovered (treated for amblyopia
and currently 0.1 logMAR or better visual acuity and 0.1 logMAR or less interocular
difference in visual acuity), or persistent amblyopic (lengthy and/or repeated attempts to treat
amblyopia with one or more treatment modalities but visual acuity remained 0.2 logMAR or
poorer and 0.2 logMAR or more interocular difference in visual acuity persisted). Four risk
factors for amblyopia were evaluated: age of onset of esotropia, delay in referral to an
ophthalmologist, age at surgery, and initial refractive error.
Early onset of esotropia might be a risk factor for persistent amblyopia because it may
represent more severe disease (Tychsen, 2005) or because early onset may result in a longer
duration of abnormal visual experience (Birch, 2003; Birch et al., 2000; Tychsen,

2005, 2007; Tychsen et al., 2004) The incidence of amblyopia was high in children
diagnosed with esotropia; 80% of the children with infantile esotropia and 74% of the
children with accommodative esotropia developed amblyopia. In neither the infantile
esotropia cohort nor the accommodative esotropia cohort, was there an association between
age at onset of esotropia and the prevalence of persistent amblyopia (Figure 7).

Figure 7
Risk factors for amblyopia in 130 consecutive children with infantile esotropia or
accommodative esotropia enrolled in a prospective longitudinal study at the time of initial
diagnosis with follow-up to a mean age of 9.5 years.(Birch et al., 2007) No ...
Delay in referral was evaluated as a risk factor for persistent amblyopia because it is known
that a shorter duration of esotropia optimizes stereoacuity outcomes (Birch, 2003; Birch et
al., 2000; Birch et al., 2005;Fawcett et al., 2000; Fawcett and Birch, 2003) and stereopsis
may reduce the risk for moderate to severe amblyopia. (Bosworth and Birch, 2003; McKee et
al., 2003) Among children who were referred for treatment within 3 months of onset of
esotropia, only 12% of the infantile esotropia cohort and 14% of the accommodative
esotropia cohort developed persistent amblyopia. Among those who were not referred for
treatment for more than 3 months post-onset, 42% of the infantile esotropia cohort and 56%
of the accommodative esotropia cohort developed persistent amblyopia; i.e., a 3.54 times
elevated risk for persistent amblyopia was associated with delayed referral (Figure 7). Within
the infantile esotropia cohort, we were also able to evaluate whether age at surgery was a risk
factor for persistent amblyopia (surgical treatment in the accommodative esotropia cohort
was rare). Very early surgery, by 6 months of age, may preserve stereopsis in children with
infantile esotropia. (Birch et al., 1998; Birch et al., 2000; Ing, 1991; Ing and Okino,
2002; Wright et al., 1994) Nonetheless, we found no significant differences in age at surgery
among those who never had amblyopia, those who recovered, and those who developed
persistent amblyopia (Figure 7).
Initial refractive error was evaluated as a risk factor for persistent amblyopia because
amblyopia may be more prevalent in children with moderate to high hyperopia (American
Academy of Ophthalmology, 2011) and because spherical anisometropia of 1.00 D or more
had been shown previously to be associated with increased risk for amblyopia in hyperopic
children with no strabismus (Weakley, 1999, 2001) Neither the infantile esotropia cohort nor
the accommodative esotropia cohort exhibited an association between initial spherical
equivalent refractive error and the prevalence of persistent amblyopia. On the other hand,

initial anisometropia was a strong risk factor for persistent amblyopia. Among children with
less than 1.00 D initial anisometropia, only 12% of the infantile esotropia cohort and 16% of
the accommodative esotropia cohort developed persistent amblyopia. Among those with 1.00
D or more initial anisometropia, 39% of the infantile esotropia cohort and 50% of the
accommodative esotropia cohort developed persistent amblyopia; i.e., a 3.13.3 times
elevated risk for persistent amblyopia was associated when anisometropia of at least 1.00 D
was present at the initial visit (Figure 7).
In a related study, we determined whether nil stereoacuity was associated with risk for poor
response to amblyopia treatment.(Bosworth and Birch, 2003) Seventy-one children were
enrolled in a prospective study of amblyopia treatment when they were 46 years old. At
enrollment 66% had nil stereoacuity; following two years of treatment, 55% remained
amblyopic. In contrast, among children who had measureable stereoacuity, only 25%
remained amblyopic. Thus the risk for persistent amblyopia was 2.2 times greater among
children with nil stereoacuity.
Taken together, these data demonstrate that risk for persistent amblyopia is elevated in
infantile esotropia and accommodative esotropia if there is a long delay between onset and
treatment and by anisometropia. The finding that the same two risk factors greatly elevate the
risk for abnormal stereoacuity and persistent amblyopia supports the hypothesis that there is
a link between binocular function and persistent amblyopia. In individuals with preserved
binocular function, the fellow eye may maintain a binocular grid of fine receptive fields so
that input to the weaker eye is not severely undersampled. Treatment plans designed to
preserve stereoacuity may help to minimize the additional loss in optotype acuity associated
with neural undersampling.
2.3 Fusional Suppression

When information from the two eyes is combined and binocular disparity is used to decode
depth, monocular position information is lost. Fusional suppression is the term coined by
McKee and Harrad (McKee and Harrad, 1993) to describe the suppression of monocular
position information in the presence of a standing non-zero binocular disparity. They were
able to measure the suppression of monocular position information in terms of diminished
visual evoked potential (VEP) amplitude in response to vernier offsets when a standing nonzero disparity was introduced. We used this paradigm to investigate the link between the
fusional suppression that occurs in normal binocular vision and the suppression of the
amblyopic eye in accommodative esotropia.(Fu et al., 2006) We chose to study children with
accommodative esotropia have a wide range of stereoacuity, from normal to nil, which
makes it easier to observe the relationships among stereoacuity, fusional suppression, and
amblyopia.

The stimulus paradigm was to record VEPs in response to oscillating vernier positional
offsets of a stripe pattern presented to one eye (Figure 8). What was varied between the test
two conditions was the pattern in the other eye, which could either have 0 min binocular
disparity or 5 min binocular disparity. Since it was a standing (static) disparity, it could only
influence VEP amplitude through its indirect effect on the vernier positional response
generated by the other eye; i.e., fusional suppression. In a cohort of 37 children with
accommodative esotropia, we found that all 8 children with normal stereoacuity and 10
children with deficient stereoacuity had normal fusion suppression (see Figure 9 for a
representative set of data from a normal control child). Amplitudes of responses to vernier
offsets were diminished in the presence of a standing binocular disparity. The vernier
responses were similar in each eye and the degree of fusional suppression was similar
regardless of which eye viewed the vernier stimulus and which eye viewed the static
disparity stimulus. Children with accommodative ET and nil stereoacuity but no amblyopia
(n=11) showed little if any fusional suppression; VEP amplitudes were similar whether or not
a standing binocular disparity was present (not shown). Results from the 8 amblyopic
children had a distinct pattern; fusional suppression was noted when the standing disparity
was presented to the fellow eye but no suppression was observed when the standing disparity
was presented to the amblyopic eye (Figure 9). These data from children with
accommodative esotropia support an association between asymmetric fusional suppression
and amblyopia. Moreover, the evidence that suppression is present and, at least in part,
involves the same mechanisms responsible for fusion in normal binocular vision suggests
that restoration of binocular function may be possible in amblyopia.

Figure 8
Schematic of the stimuli used to assess fusional suppression.(Fu et al., 2006) Stimuli were
dichoptic (anaglyphic) multi-bar vernier targets. When there was no standing binocular
disparity present (left), 5 static segments interspersed with 4 oscillating ...

Figure 9
VEP responses to monocular oscillating vernier offsets recorded from a child with normal
vision (left) and an amblyopic child (right) with 0 or 5 min standing binocular disparity.(Fu
et al., 2006) For the child with normal vision, vernier responses are ...

2.4 Gaze Instability, Binocular Vision, and Amblyopia

Abnormal visual experience during infancy or early childhood that interferes with binocular
fusion is invariably associated with gaze instability, most often fusion maldevelopment
nystagmus syndrome (FMNS).(Tychsen et al., 2010) FMNS is a commonly associated with
strabismus and amblyopia. It is characterized by a conjugate horizontal slow-phase
nasalward drift of eye position, with temporalward corrective flicks. Because the slow drift is
always nasalward, a switch in fixation eye results in an immediate reversal of the direction of
the drift. This feature makes it easily distinguishable from infantile nystagmus (INS). Studies
of non-human primates demonstrated that FMNS can result from the loss of binocular
connections in the striate cortex that occurs in experimental models of strabismus and
anisometropia. In a series of elegant experiments, Tychsen and colleagues (Tychsen et al.,
2010) have demonstrated that the prevalence and severity of FMNS increases as the period of
decorrelated abnormal binocular experience is lengthened, with a duration in primates that is
equivalent to 3 months in humans resulting in 100% prevalence. Tychsen et al (Tychsen et
al., 2010) propose that the binocular maldevelopment of the striate cortex is passed on to
downstream extrastriate regions of cerebral cortex that drive conjugate gaze, including
medial superior temporal area and that unbalanced monocular activity may result in one
hemisphere becoming more active than the other, resulting in nasalward drift bias that
typifies FMNS.
We evaluated the link between binocular vision, gaze instability, and amblyopia in a group of
33 children 5 years of age with hyperopic anisometropia.(Birch et al., 2012) Hyperopic
anisometropia places the child at risk for abnormal stereoacuity and microstrabimsus, which
is noted clinically as a temporalward flick as each assumes fixation on cover testing. The
dominant hypothesis is that abnormal sensory experience due to anisometropia leads to
foveal suppression, which in turn leads to microstrabimsus.(American Academy of
Ophthalmology, 2011) We proposed an alternative hypothesis; namely, that disruption of
bifoveal fusion by anisometropia has a direct effect on ocular motor function. Fixation
stability was measured using the Nidek MP-1 microperimeter, which combines a nonmydriatic infrared fundus camera to obtain real time retinal images and a liquid crystal
display (LCD) to present a fixation target. The fixation target was a 1 radius red circular
ring, displayed in the center of the LCD screen,. Children were provided a chin rest and
forehead rest and were instructed to fixate steadily at the center of the ring. Initially, a
reference fundus image with 1 pixel (0.1 deg) resolution was captured, and a high contrast
retinal landmark in the frozen image was identified by the examiner. During the 30 sec test
period, software calculated shifts in horizontal and vertical eye position between the
reference image and the real-time fundus image at 25 Hz. A scattergraph of the fixation
points was displayed and fixation stability was quantified as the area of the 95% bivariate

contour ellipse (BCEA); i.e. an ellipse that provided the best fit to the boundary of 95% of
the 750 fixation points acquired during the 30 sec test interval. Stereoacuity was measured
using the Preschool Randot Stereoacuity Test. Examples of the fixation stability data
obtained from 3 children with hyperopic anisometropia are shown in Figure 10.

Figure 10
Examples of fixation stability obtained from 33 5- to 9-year-old children with hyperopic
anisometropia using the Nidek MP-1 microperimeter.(Birch et al., 2012) On each image, the
small blue dots mark the location of the 750 fixation points acquired during ...
All children with normal stereoacuity had normal fixation stability (Figure 11). Children with
abnormal stereoacuity had unstable fixation, and children with nil stereoacuity had the most
instability (Figure 11). Although there was moderate variability among children, there was a
strong correlation between stereoacuity and fixation instability (BCEA area); r s=0.54,
p=0.002. We were also able to export the raw eye movement data to analyze waveforms and
categorize eye movements as normal (with or without square-wave oscillations), FMNS, or
INS (Figure 12).

Figure 11
Fixation instability during 30 sec of attempted steady fixation for 33 children with hyperopic
anisometropia.(Birch et al., 2012) Age-matched normal controls had a mean BCEA = 2.1
0.9 deg2 (yellow line), with a 95% tolerance range of 0.2 to ...

Figure 12
Eye position records derived from the Nidek MP-1 for the 3 anisometropic children shown
in Figure 10.(Birch et al., 2012) The top trace shows eye position for the child with normal
fixation stability (Figure 10, left); overall, fixation is accurate, with ...
None of the children with normal stereoacuity had FMNS waveforms, 67% of children with
abnormal stereoacuity had FMNS waveforms, and nearly all of the children with nil
stereoacuity had FMNS waveforms (Figure 13). Thus, the temporalward flick that is seen
during cover testing in children with hyperopic anisometropia is likely evidence of a direct

effect of disruption of bifoveal fusion by anisometropia on ocular motor function; i.e., the
decorrelation of retinal images caused by anisometropia results in FMNS. Note that this
FMNS is often very small in amplitude, making it difficult to appreciate clinically except
with close observation, like during cover testing. More importantly, in most children with
anisometropia, we observed FMNS only in intermittent, small amplitude bursts, so it may not
always be obvious during a brief clinical examination. Our data are consistent with the model
of FMNS proposed by Tychsen, Wong, and colleagues in which correlated visual experience
is necessary for the development of stereopsis and balanced gaze.(Tychsen et al., 2010)
Decorrelated visual experience, due to anisometropia can lead to stereoacuity deficits and the
gaze asymmetry of FMNS, a disruption of ocular motor development. We propose that the
temporalward re-foveating FMNS flicks may mimic microstrabismus during cover testing
but are actually an ocular motor abnormality that directly results from binocularly
decorrelated visual experience. If this hypothesis is correct, our proposal that binocular
dysfunction plays a primary role in amblyopia leads us to also expect a relationship between
amblyopia and fixation instability.

Figure 13
Prevalence of FMNS among 33children with hyperopic anisometropia divided into 3 groups
based on their stereoacuity. (Birch et al., 2012)
We investigated the relationship between fixation instability and amblyopic visual acuity
deficits. Carpineto et al. (Carpineto et al., 2007) reported that fixation instability was present
in some children with microstrabimsus and amblyopia. More recently, Gonzalez et al.
(Gonzalez et al., 2012) reported significantly larger fixation areas (more instability) in
amblyopic eyes of 13 adults compared with fellow eyes and control eye. We quantified
fixation stability in 89 amblyopic and nonamblyopic children with strabismus,
anisometropia, or both and an age-matched normal control group using the Nidek MP-1
microperimeter to acquire eye position and BCEA to quantify fixation instability.
(Subramanian et al., 2012) During attempted steady fixation with their amblyopic eyes,
children had 35X greater fixation instability (larger BCEA areas) than when fixing with
their fellow eyes and compared with normal controls fixing monocularly (Figure 14).

Figure 14

Mean fixation areas (95% BCEA) for amblyopic, non-amblyopic and normal control
children.(Subramanian et al., 2012) Compared with children with strabismus, anisometropia,
or both who were nonamblyopic, amblyopic children had significantly greater fixation ...
There was a statistically significant positive correlation between visual acuity and BCEA (r =
0.58; p < 0.0001) for amblyopic eyes; amblyopic eyes with poorer visual acuity had greater
fixation instability and, thus, larger and wider bivariate contour ellipse areas. Categorical
severity of fixation instability has been previously reported to be associated with depth of
amblyopia (Carpineto et al 2007). On the other hand, BCEA in 13 adults with amblyopia was
not correlated with amblyopic eye visual acuity, although interocular differences in visual
acuity were correlated with BCEA. (Gonzalez et al., 2012) Additionally, we found that
amblyopic eyes had highly elliptical BCEAs, with a much longer horizontal than vertical
axis, consistent with abnormal development of the ocular motor system. Fixation instability
along both the horizontal and vertical axes was about 1.52X larger for amblyopic eyes than
normal control eyes. This finding is consistent reports of predominantly horizontal squarewave oscillations and FMNS in amblyopic children. (Felius et al., 2011; Felius et al., 2012)
2.5 Motor Skills in Amblyopia

Deficits in fine motor skills have been widely reported to be present in amblyopic
individuals.(Grant and Moseley, 2011) Most of these studies aimed to evaluate the utility and
value of rehabilitation of the amblyopic eye as a spare eye and so relied on testing
amblyopic individuals when they are forced use the amblyopic eye alone. However, if
amblyopia is primarily the result of binocular dysfunction, we would also expect to see such
deficits in binocular task performance. We evaluated the effects of amblyopia on motor skills
under binocular viewing conditions (OConnor et al., 2010a, b); specifically we evaluated
performance on the Purdue pegboard (number of pegs placed in 30 seconds) and bead
threading (time to thread a set number of large and small beads in 143 individuals, 47 of
whom had manifest strabismus and 30 of whom had amblyopia. (21 strabismic amblyopia; 9
anisometropic amblyopia). Performance on the fine motor skills tasks was related to
stereoacuity, with subjects with normal stereoacuity performing best on all tests (Figure 15).
Individuals with amblyopia were significantly slower on both bead tasks than were those
without amblyopia. However, when the statistical analysis was repeated with stereoacuity as
a covariate, the difference between amblyopic and nonamblyopic individuals on the bead
task was no longer statistically significant. This result is in agreement with a previous report
that fine motor skill performance was related to the level of stereoacuity but not to the
presence of unilateral vision impairment in 3- to 4-year-old children. (Grant et al., 2007)
Webber et al.(Webber et al., 2008a) have also reported that both the amblyopia and
stereoacuity deficits were associated with reduced performance on fine motor skill tasks.

Taken together, these results confirm that children with binocular dysfunction have impaired
fine motor skills and that this impairment is more closely related to the severity of binocular
dysfunction than to the severity of amblyopia.

Figure 15
Performance on fine motor tasks by amblyopic and nonamblyopic individuals with three
levels of binocular function.(OConnor et al., 2010a, b) There was a significant difference in
performance on the Purdue Pegboard and the large and small bead ...
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3. Binocular Treatment of Amblyopia
As noted above, current treatments for amblyopia are not sufficient to achieve normal visual
acuity for 1550% of amblyopic children. Even when normal visual acuity is achieved,
amblyopia often recurs. Older children and adults with persistent amblyopia are rarely
treated because the predominant mindset is that decorrelated binocular visual experience and
habitual suppression of the amblyopic eye has caused permanent loss of binocular cells and
changed the functional profile of cortical cells responsive to the amblyopic eye. However, the
evidence discussed in Section 2 suggests, although there is binocular dysfunction, the
capacity for binocular interaction is not absent. Morever, interocular suppression of the
amblyopic eye may be preventing binocular interaction. Taken together, these data suggest
that there is a need for a new, binocular approach to amblyopia treatment. The goal is to
reduce the prevalence of residual amblyopia and prevent amblyopia recurrence.
3.1 Perceptual Learning

One new approach is perceptual learning. The effect of repeated practice on perceptual
performance has become a focus of amblyopia treatment, particularly for adults and older
children who have abandoned traditional approaches to treatment. It is clear that normal
controls in the research laboratory who repeatedly practice on a demanding visual task
achieve significant and durable improvement in their visual performance on that specific
task.(Levi, 2012) More relevant, is the evidence that amblyopic individuals who practice a
perceptual task improve not only on that specific task, but also have generalized
improvement when tested with other perceptual tasks.(Levi, 2012)
Perceptual learning as a treatment for adult amblyopia has typically been conducted with the
fellow eye patched. The visual task for training is designed to engage the amblyopic

individual in making fine discriminations and to provide repeated exposure over many hours.
It has been suggested that perceptual learning is simply an extension of the traditional effects
of patching therapy, where the amblyopic individual must accomplish many visual
discriminations in everyday life. The argument that perceptual learning succeeds where
everyday experience fails in amblyopic adults is that the less plastic brain of the adult
requires attention and action using the amblyopic eye, supervised with feedback in order to
provide effective treatment.(Levi, 2012) Even with 4050 hours of perceptual learning, most
adults achieve only 0.10.2 logMAR improvements in visual acuity (12 lines).(Levi, 2012)
The limited improvement in visual acuity, the dedicated time required for treatment, and the
boredom/compliance issues associated with repetition of a perceptual task, have limited the
application of perceptual learning as a routine treatment for amblyopia. To overcome these
limitations, research has turned toward the evaluation of video games as a potential treatment
for amblyopia in adults. The rationale is that action video games, in particular, engage visual
attention and require demanding visual discriminations in a similar way to the more standard
perceptual learning paradigms, but is able to sustain prolonged participation because of the
story lines, varied visual tasks, and rewards provided by the games for making correct
discriminations. A recent evaluation of an of-the-shelf action game (Medal of Honor: Pacific
Assault) found that just 20 hours of play with the fellow eye patched resulted in a mean
improvement of 0.15 logMAR and that additional small gains in visual acuity continued in
some amblyopic individuals through 80 hours of play (Figure 16).(Li et al., 2011)
Interestingly, though, similar gains in visual acuity were experienced by amblyopic adults
playing a non-action video game (Sim City) or performing a simple perceptual learning
grating acuity task while patched. Patching alone was not sufficient to improve visual acuity
(Figure 16). Of course, the idea of visual stimulation as a part of amblyopia is not new. For
many years, eye care professionals have placed an emphasis on the child performing near
activities while patched; i.e., the role of active, attentive vision in amblyopia recovery has
been appreciated for many years.

Figure 16
Improvement in visual acuity with patching in 18 amblyopic adults while playing an action
video game or a non-action video game for 20 hours. Also shown is the visual acuity
improvement achieved with 20 hours of patching while practicing a grating acuity ...
3.2 Treating Binocular Dysfunction Amblyopia

In most studies to date, perceptual learning has been applied monocularly with the same aim
as patching therapy, to improve visual acuity of the amblyopic eye. Some improvements in
stereoacuity have been found to accompany the amblyopic eye visual acuity improvement,
(Levi, 2012) similar to the modest gains in stereoacuity that have been reported to
accompany successful patching therapy. (Wallace et al., 2011b) However, a growing
appreciation of the role of decorrelation of binocular stimulation in suppression of the
amblyopic eye has motivated a reformulation of amblyopia treatment. Decorrelated binocular
experience may not only compromise binocular function but also contribute to or cause the
monocular deficits. In other words, we have come to view binocular dysfunction as the
primary deficit and the monocular visual acuity deficit as secondary. In this framework,
patching, with or without perceptual learning treatment, treats the secondary monocular
visual deficits but does not directly address the primary binocular deficit. We wanted to find
a new approach to treatment for amblyopia that would not only improve visual acuity of the
amblyopic eye but also provide repeated, correlated binocular visual experience. Unless the
binocular dysfunction is treated, abnormal binocular vision may result in residual amblyopia,
and may trigger recurrence of amblyopia.
Reducing contrast to the fellow eye to equate the visibility between amblyopic and fellow
eyes can allow binocular contrast summation, (Baker et al., 2007) and suprathreshold
binocular interactions in motion coherence and orientation discrimination tasks (Mansouri et
al., 2008) to occur in at least some amblyopic individuals. This suggests that the absence of
binocular interactions in amblyopia reported in the literature may have been due to the
imbalance in the monocular signals rather than to an absence of capacity for binocular
interaction. Hess and colleagues (Hess et al., 2010) reported improvement in visual acuity
and binocular vision following several weeks of practice with a dichoptic motion coherence
task presented via video gaming goggles. For the initial practice session, the contrast of the
randomly moving dots in the fellow eye was reduced to about 10% while the amblyopic eye
coherent dots were presented at 100% contrast. This allowed the amblyopic eye to breakthrough and observers were able to experience binocular vision. As the 10 amblyopic adults
began to experience binocular vision, the contrast in the fellow eye was gradually increased
during 3 or 4 sessions per week for 3 to 5 weeks until the two eyes worked together with
more evenly matched contrasts. In addition to improvements in binocular combination,
visual acuity improved 0.1 to 0.7 logMAR (Figure 17) and stereoacuity improved in 6 of the
10 adults. Knox et al (Knox et al., 2012) used the same device to administer one week of
dichoptic treatment but used a more interesting video game task (Tetris). As with the motion
coherence task, the contrast of the fellow eye image was reduced to allow binocular vision to
occur. Five 1-hour practice sessions during a one week were provided. The 14 amblyopic
children (511 years old) has a median improvement of 0.09 logMAR in visual acuity (about

1 line) and 9 of the 14 also had improvements in stereoacuity (Figure 17). Most recently To
and colleagues (Hess et al., 2012; To et al., 2011) moved the dichoptic Tetris game to an iPod
platform to allow for more comfortable play and play at home. They evaluated the effects of
dichoptic Tetris practice (with low contrast to the fellow eye) in 10 amblyopic adults and
found found a median visual acuity improvement of 0.2 logMAR after 1019 one hour
sessions (Figure 17); 7 of the 10 adults also had improvements in stereoacuity. Taken
together, these data support the hypothesis that a binocular approach to treatment of
amblyopia can be successful. Repeated experience with dichoptic perceptual tasks led to
modest improvements in monocular visual acuity and, in some cases, improved stereopsis.

Figure 17
Visual acuity improvement following 520 hours of dichoptic training to amblyopic
individuals using video game goggles to make motion coherence judgments (Hess et al.,
2010) or play Tetris (Knox et al., 2012) or using a lenticular overlay on an ...
To date, this approach largely has been limited to the laboratory, with the use of video game
goggles and the need for administration of practice sessions by trained staff, and limited to
adults and school-age children. We wanted to extend binocular treatment to the preschool age
range, to be used as an adjunct treatment along with patching (at separate times of day) to
reduce residual amblyopia and to reduce risk for recurrence of amblyopia. The extension to
an iPod platform and lenticular display was a step toward incorporating dichoptic training
into clinical settings for adults and school-age children. However, it is difficult to extend the
lenticular iPod to preschool children because the iPod requires fine motor skills and the
lenticular display requires precise and steady head position to provide dichoptic stimulation.
We worked with Hess and To to adapt the dichoptic Tetris game for use on the larger iPad
format, which is more compatible with the immature fine motor skills of young children, and
anaglyphic dichoptic separation, which is not dependent on head position. We are currently
studying the effects of anaglyphic dichoptic training on amblyopia and risk for recurrence in
3- to 5-, 6- to 8-, and 9- to 11-year old children with strabismic, anisometropic, or combined
mechanism amblyopia.(Birch et al., 2013) Many of the children we are studying were
enrolled in our prospective longitudinal study of visual development at time of initial
diagnosis of strabismus or anisometropia. For these children we have detailed histories of
visual acuity, treatment regimens, and response to treatment. An example of a childs visual
acuity history and visual acuity improvement with the anaglyphic dichoptic training are
shown in Figure 18. While still preliminary, our results from 23 children are consistent with
the data from the published laboratory studies of small cohorts of amblyopic adults and

school-age children. Many of the children have improved stereoacuity after only 1520 hours
of dichoptic practice, including some who achieve coarse stereopsis for the first time. In
addition, there is an improvement in in visual acuity of 0.10.4 logMAR. That rehabilitation
of binocular interaction is accompanied by improved monocular visual acuity supports the
hypothesis that binocular dysfunction plays a pivotal role in amblyopia, an appreciation of
which is not currently reflected in clinical practice.

Figure 18
Visual acuity data from a child with anisometropic amblyopia before and after dichoptic
training.(Birch et al., 2013) On the intitial visit at 4.4 years old, best corrected visual acuity
for the amblyopic eye was 0.9 logMAR. Treatment with glasses, patching, ...
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4. Future Directions
As summarized above, there is accumulating evidence that amblyopia and binocular function
are linked and several noteworthy clues that binocular dysfunction is primary and monocular
visual acuity loss is secondary. This new understanding of amblyopia provides a foundation
for a broadened scope of research and for crafting more effective treatments. The last 15
years has seen an explosion of randomized clinical trials to evaluate treatments for children
with amblyopia, and a shift from treatment based on consensus to evidence-based treatment.
Nonetheless, there remain many unanswered questions about amblyopia screening,
diagnosis, and treatment.
4.1 Screening for Amblyopia

Screening for amblyopia is a part of the regular well-child visit recommended by the
American Academy of Pediatrics. Screening by a pediatrician or family care practitioner can
identify amblyopia at a time when treatment is most effective. Screening improves vision
outcomes. In a population-based, randomized longitudinal study, repeated early screening
resulted in a 60% decreased prevalence of amblyopia and improved visual acuity outcome at
age 7 years compared with surveillance only until school entry.(Williams and Harrad,
2006; Williams et al., 2001; Williams et al., 2008) Amblyopia can be treated more effectively
when treated early; the same study found a 70% lower prevalence of residual amblyopia after
treatment when therapy was initiated before age 3 years. (Williams et al., 2001; Williams et
al., 2002, 2003) However, pediatricians and family care practitioners experience considerable

difficulties in screening for amblyopia.(Tingley, 2007) Most primary care providers in the
United States still use visual acuity charts as their primary approach to vision screening for
amblyopia.(Wall et al., 2002) Unfortunately, reading letters or numbers on a visual acuity
chart requires a verbal, cooperative child and is not routinely successful in children under 5
years old, too late for the most effective therapy. When the testing is conducted earlier,
nonstandard symbols or chart formats are used and often they are not presented in the linear
or crowded formats needed to detect mild amblyopia. Table 2 summarizes recent studies that
document how these difficulties impact the vision screening provided by primary care
physicians to preschool children.

Table 2
Reported success rate for vision screening of preschool children by pediatricians and family
care practitioners.
Automated devices, like the SureSight and PlusOptix have been developed to try to
improve upon visual acuity testing, by providing a simple approach to screening for
refractive error risk factors, rather than screening for amblyopia directly. These devices are
attractive because they are designed for use by pediatric nurses, pediatric medical assistants,
and even lay people. However, these automated devices miss many children with amblyopia
and many normal children are sent to the ophthalmologist for an unnecessary eye
examination, further increasing the cost of health care. For example, in the combined
population-based cohorts of 2- to 6-year old children from the NIH-sponsored Multi-Ethnic
Pediatric Eye Study (MEPEDS) and the Baltimore Pediatric Eye Study (BPEDS) (N=5710),
only 14% of children with 1.00 D anisometropia had amblyopia and only 60% of children
with 2.00 D anisometropia had amblyopia;(Cotter et al., 2011) i.e., screening for
anisometropia and will have low specificity for amblyopia. In addition, amblyopia risk factor
analysis failed to identify hyperopia a significant risk factor for unilateral amblyopia.(TarczyHornoch et al., 2011) Because refraction screening devices cannot directly detect strabismus
or amblyopia, many at risk children are referred for comprehensive ophthalmic
examinations at considerable cost in time and money to the family. Once these at risk
children are referred, they often are monitored with regularly scheduled ophthalmic
examinations for years, even though the data suggest that only 9%18% of the children at
risk will ever develop amblyopia.

Recently, Hunter and colleagues developed an alternative approach to screening for

amblyopia, a binocular birefringence scanner called the Pediatric Vision Scanner or
PVS.(Hunter et al., 2004; Loudon et al., 2011; Nassif et al., 2004; Nassif et al., 2006)
Simultaneous retinal birefringence scans of both eyes detect whether fixation of a target is
foveal (central), steady, and maintained by identifying the unique polarization signal created
by the radially arranged Henle fibers (photoreceptor axons) that emanate from the fovea.
(Hunter et al., 2004; Loudon et al., 2011; Nassif et al., 2004) In a pilot study of the PVS,
Loudon et al.(Loudon et al., 2011) reported that all normal control children had at least 4 of 5
scans consistent with bifoveal fixation, and that 62 of 64 amblyopic children failed to exhibit
birefringence (97% sensitivity to amblyopia). The PVS was able to detect amblyopia even in
the 22 children with anisometropic amblyopia and no strabismus (20/22; sensitivity = 91%)
and birefringence was normal in children with anisometropia without amblyopia (11/12;
specificity = 92%). We have independently confirmed these PVS results in anisometropic
children with no strabismus.(Yanni et al., 2012) Moreover, these data are consistent with the
association between fixation instability and amblyopia in both anisometropic and strabismic
individuals (Section 2.4).(Birch et al., 2012; Subramanian et al., 2012) Taken together, the
pilot data suggest that binocular birefringence screening could provide more accurate
identification of children who need ophthalmological intervention.
4.2 Diagnosis of Amblyopia

Diagnosis of amblyopia relies on the measurement of visual acuity. Reduced best corrected
visual acuity in presence of an amblyogenic factor (usually strabismus or anisometropia)
with no other ocular or visual cortical abnormality is currently the critical component of
amblyopia diagnosis. However, most children <3 years old and some older children cannot
complete a visual acuity test. Instead, the clinical diagnosis of amblyopia in children <3
years old must rely on fixation preference.
Recently, fixation preference has been disparaged as a method for assessing amblyopia. The
basis for questioning the value of fixation preference is found in two large (n=9970)
population-based screening studies, MEPEDS and BPEDS.(Cotter et al., 2009; Friedman et
al., 2008) Both included primarily normal children; only 44 had 2 lines interocular
difference in visual acuity. With such a small sample of primarily mild amblyopia, it is not
surprising that they reported low sensitivity of fixation preference. Only a handful had
strabismus, so most fixation preference testing relied on the more difficult induced tropia
(prism) test. Another limitation was that fixation preference was tested without optical
correction while visual acuity was tested with optical correction. Given these limitations, it is
not surprising that they reported low specificity. Data collected from clinical cohorts support
much higher sensitivity and specificity for detection amblyopia by fixation preference in

cohorts of children with strabismus (sensitivity 73%93%; specificity 78%97%).(Birch and

Holmes, 2010; Kothari et al., 2009; Procianoy and Procianoy, 2010; Sener et al.,
2002; Wright et al., 1986) As noted in Section 1.2, 95% of amblyopic children <3 years old
have strabismus,(Birch and Holmes, 2010) so we anticipate high sensitivity and specificity of
fixation preference in this age range where visual acuity cannot be tested with standard
optotypes. Whether small changes in fixation preference can be used to track treatment
response remains an open question. Given the scarcity of evidence for treatment effects and
risks of amblyopia treatment (e.g., reverse amblyopia) in the <3 year age range, it is
imperative to answer this question before we can begin to build an evidence base for
treatment of amblyopia in children <3 years old.
4.3 Optimizing Treatment for Amblyopia

The cornerstone of amblyopia treatment is patching the fellow eye to force use of the
amblyopic eye. Recent randomized clinical trials have provided and extensive knowledge
base for treatment of amblyopia in children over 3 years old.(Holmes et al., 2006; Repka and
Holmes, 2012; Stewart et al., 2011) Nonetheless, the high prevalence of persistent residual
amblyopia and recurrent amblyopia underscore the need for more effective treatments. Our
current focus is to provide regular binocular experience to treat binocular dysfunction by
adjusting the contrast of dichoptic images to balance sensitivity differences between the
amblyopic and fellow eyes and allow binocular interaction (Section 3.2). However, it is
improbable that sensitivity differences are the only limiting factor. Other approaches to
treating binocular dysfunction, tailored to the specific constellation of deficits present in the
amblyopic individual may be more effective. In addition, it may prove impossible to fully
restore binocular interaction. Such an outcome would shift the emphasis toward amblyopia
prevention. We know, for example, that early surgery for infantile esotropia can preserve
binocular function and reduce the risk for persistent amblyopia.(Birch and Stager,
2006; Birch et al., 2004) Clinical pearls, such as the reduced risk for recurrent amblyopia
when patching therapy is tapered rather simply halted when the child attains equal visual
acuities, may also point to new insights for the design of effective binocular treatments.
Clearly, there is a need for a broader understanding of the effects of decorrelated binocular
visual experience on the developing sensory and motor systems, the role of suppression in
various forms of amblyopia, and the contribution of binocular dysfunction to residual and
recurrent esotropia.
Go to:
5. Summary

Amblyopia is widely viewed as a monocular disorder and treatments for amblyopia, many of
which have been used for centuries, have traditionally focused on forcing use of the
amblyopic eye to recover monocular visual acuity. Although this approach has had
substantial success, and is supported by recent evidence from randomized clinical trials of
patching and atropine treatment, many amblyopic individuals are left with residual visual
acuity deficits, ocular motor abnormalities, deficient fine motor skills, and high risk for
recurrent amblyopia. Converging evidence points to the pivotal role of decorrelated binocular
experience in the genesis of amblyopia and the associated residual deficits. These findings
suggest that a new treatment approach designed to treat the binocular dysfunction as the
primary deficit in amblyopia may be needed.
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Supplementary Material
01

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02

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Acknowledgments
This work was supported by grants from the National Eye Institute (EY05236 and
EY022313), Thrasher Research Fund, Pearle Vision Foundation, One Sight Foundation,
Knights Templar, and Fight for Sight. The research depended on many important
contributions by past and present post-doctoral fellows, the Dallas-area pediatric
ophthalmologists who referred patients to the research projects and collaborated in data
collection and analysis, research assistants, and interns. This research relied on the many
contributions of the families of amblyopic children who have participated in these studies.
Go to:
Footnotes
The research was conducted at the Retina Foundation of the Southwest.
*

Please note that the Retina Foundation of the Southwest will be moving to new building late in 2012 or
early in 2013.
Conflicts of Interest

None.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for
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